ADCs can be used for the local delivery of drugs that can kill or inhibit the growth or division of target tissues or cells. The use of ADCs for the local delivery of cytotoxic or cytostatic agents to kill or inhibit tumour cells in the treatment of cancer has been described (see Anticancer Research (1999) 19:605-614; and Adv. Drug Delivery Rev. (1997) 26:151-172). Theoretically, the approach allows targeted delivery of a drug moiety to tumours, and intracellular accumulation therein, where systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumour cells sought to be eliminated (Lancet pp. (Mar. 15, 1986):603-05; and “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” (1985) in Monoclonal Antibodies '84: Biological And Clinical Applications, A. Pinchera et al. (ed. s), pp. 475-506). Maximal efficacy with minimal toxicity is therefore the ideal goal.
Early work on ADCs discovered that chemical linkages used often resulted in the loss of a drug's potency in vitro and in vivo. Thus, it was realised that a drug would ideally need to be released in its original form in order to be a useful therapeutic. Work thus concentrated on the nature of the chemical linker between the drug and the antibody. This approach was described in Science (1993) 261:212-215 showing that antibody-doxorubicin conjugates, prepared with linkers, could be used to treat mice bearing human tumour xenografts.
Further efforts to design and refine ADCs generally focused on the selectivity of monoclonal antibodies (mAbs), the linkers used to link the antibody to the drug and/or drug-releasing properties. Both polyclonal antibodies and monoclonal antibodies have been reported as useful in these strategies. Drugs that have been used include daunomycin, doxorubicin, methotrexate, mitomycin, neocarzinostatin and vindesine. Toxins have also been used in antibody-toxin conjugates including bacterial toxins—such as diphtheria toxin; plant toxins—such as ricin; small molecule toxins—such as geldanamycin, macrocyclic depsipeptides and calicheamicin. The toxins may effect their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands.
An example of successful monoclonal antibody therapy is Herceptin® (trastuzumab), a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2 (ErbB2) (see Science (1985) 230:1132-9; and Science (1989) 244:707-12). Although Herceptin® has been a breakthrough in treating patients with ErbB2-overexpressing breast cancers that have received extensive prior anti-cancer therapy, the majority of the patients in this population fail to respond or respond only poorly to Herceptin® treatment. Studies in tumour bearing mice have revealed that only tumour cells around the tumour neo-vasculature are targeted by the antibody in vivo.
It is now accepted that the growth of solid tumours is dependent on their capacity to acquire a blood supply, and much effort has been directed towards the development of agents (known as anti-angiogenics) that disrupt this process. More recently, it has become apparent that targeted destruction of the established tumour vasculature is another avenue for therapeutic intervention.
The present invention relates inter alia to improvements in ADCs, especially in ADCs that be used to target vascular tumours.